Pramipexole as a treatment for cocaine craving

ABSTRACT

Disclosed herein are methods foe reducing stimulant dependency or craving, involving administration of a therapeutically-effective amount of a dopamine agonist, such as pramipexole.

This application claims the benefit of Provisional Application No.60/156,860 filed Sep. 30, 1999.

BACKGROUND OF THE INVENTION

This invention relates to methods for the treatment of cocaine craving.

Cocaine is a highly addictive pyschostimulant that causes sensations ofeuphoria and craving, resulting in physiological as well aspsychological damage. Although cocaine use leads to a multitude ofphysiological complications, its primary target of action is the centralnervous system. Cocaine withdrawal following abstinence causes, amongother symptoms, an intense craving for the abused drug, which in turnfrequently results in the relapse into renewed drug use. Epidemiologicalstudies point to a high incidence of multiple substance abuse amongcocaine users, a finding that has significant societal and medicalrepercussions.

To date, approved pharmacotherapies for cocaine abuse and dependencehave proven scarce despite the acute need for such therapies.

SUMMARY OF THE INVENTION

In general, the invention features methods for treating stimulantdependencies, such as cocaine craving, by administering atherapeutically-effective amount of a dopamine agonist, for example,pramipexole.

In one aspect, the invention provides a method of treating a patient(for example, a human) with a stimulant dependency by administering atherapeutically-effective amount of pramipexole to the patient. Inpreferred embodiments of this aspect, the stimulant dependency is astimulant craving and the stimulant is cocaine.

In a related aspect, the invention provides a method of treating a humandiagnosed with cocaine craving by administering atherapeutically-effective amount of pramipexole to the human.

In preferred embodiments of both of the above aspects of the invention,the method further includes administering a therapeutically-effectiveamount of an antidepressant or an anticonvulsant, for example,lamotrigine.

By “treating” is meant the medical management of a patient with theintent that a cure, amelioration, or prevention of a dependency or arelapse or associated disease, pathological condition, or disorder willresult. This term includes active treatment, that is, treatment directedspecifically toward improvement of the dependency or associated cure ofa disease, pathological condition, or disorder, and also includes causaltreatment, that is, treatment directed toward removal of the cause ofthe dependency or associated disease, pathological condition, ordisorder. In addition, this term includes palliative treatment, that is,treatment designed for the relief of symptoms rather than the curing ofthe dependency, disease, pathological condition, or disorder; preventivetreatment, that is, treatment directed to prevention of the dependencyor associated disease, pathological condition, or disorder; andsupportive treatment, that is, treatment employed to supplement anotherspecific therapy directed toward the improvement of the dependency orassociated disease, pathological condition, or disorder. The term“treating” also includes symptomatic treatment, that is, treatmentdirected toward constitutional symptoms of the dependency or anassociated disease, pathological condition, or disorder.

By “stimulant” is meant any substance that temporarily increasesfunctional activity, and preferably cardiac, respiratory, cerebral,nervous, vascular, motor, or vasomotor functional activity. Preferredstimulants include, without limitation, cocaine, amphetamines,methamphetamine, and methylphenidate.

By “therapeutically-effective amount” is meant an amount of apramipexole compound sufficient to produce a healing, curative, orameliorative effect either in the treatment of a stimulant dependency orin the symptoms of a stimulant dependency, for example, cocaine craving.

By “dependency” is meant any form of behavior that indicates an alteredor reduced ability to make decisions resulting, at least in part, fromthe use of stimulants. Representative forms of dependency behavior maytake the form of antisocial, inappropriate, or illegal behavior andinclude those behaviors directed at the desire, planning, acquiring, anduse of stimulants. This term also includes the psychic craving for adrug that may or may not be accompanied by a physiological dependency,as well as a state in which there is a compulsion to take a drug, eithercontinuously or periodically, in order to experience its psychic effectsor to avoid the discomfort of its absence. Forms of “dependency” includehabituation, that is, an emotional or psychological dependence on acompound to obtain relief from tension and emotional discomfort, as wellas physical or physiological dependence, that is, use of a compound toprevent withdrawal symptoms.

By “craving” is meant a behavior that reflects a consuming desire,longing, or yearning for a stimulant. This term may refer to aspects ofbehaviors that are components of a dependency.

The present invention provides a number of advantages. Importantly, itprovides one of the first therapeutics for the treatment of stimulantcravings (such as cocaine craving). In addition, the pramipexoleutilized herein is non-toxic, is pharmocokinetically understood, and isknown to be well tolerated by humans, as is evidenced by its approvalfor the treatment of Parkinson's Disease.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic illustration of the molecular structure ofpramipexole, marketed as Mirapex in the United States.

DETAILED DESCRIPTION OF THE INVENTION

The invention described herein features methods involving theadministration of pramipexole (or other dopamine-D3/D2 agonists) for thetreatment of stimulant dependency, and preferably for the treatment ofcocaine craving and its symptoms, as well as cocaine dependency andassociated self-destructive behaviors.

Described below is an example of the successful use of pramipexole forthe treatment of cocaine craving and related symptoms. This example isprovided for the purpose of illustrating the invention, and should notbe construed as limiting.

Treatment of Cocaine Craving Using Pramipexole

Mr. A, a 34 year-old single, successful business man, was referred forevaluation of possible bipolar disorder. Currently depressed, he had inthe previous year brought financial ruin on himself by a pattern ofcocaine freebasing and sexual and other extravagance that absorbednearly one million dollars.

Along with current major depression, persisting cocaine craving but rareuse, and a question of past primary or secondary (to substance abuse)mania, he manifested an extraordinary movement disorder with constantrestlessness and thrashing of his legs, leaving the inner aspects of hisknees and thighs bruised and discolored with hematomas in various stagesof evolution and resolution.

For the restless legs, he bad consulted a neurologist who diagnosed“pre-parkinsonism” presumed secondary to neurological damage fromcocaine. The disfiguring movements limited his ability to return to andconduct business.

Previously, he had failed to respond to or tolerate most of the newgeneration of antidepressants. Treatment was begun with lamotrigine upto 200 mg with modest improvement in mood. Given his severe restlesslegs syndrome and persisting depression, pramipexole was added, titratedto 1.5 mg a day in divided doses.

In response to this treatment, his leg movements quieted substantially,his mood brightened, and he reported that these were the first days in ayear that he awoke without craving cocaine, a benefit sustained for oneyear on this drug, combined with 75 mg of lamotrigine. During thesubsequent year, Mr. A. reported one day of non-compliance when he wasout of town without his medication. That night, for the first time, hedreamt about cocaine and the next day experienced a renewed craving onawakening which resolved when treatment was restored.

Although he faces an array of financial and business challenges, hismood following treatment is nearly euthymic, his leg movements at worstresemble mild restlessness, and his cocaine craving remains abolished.

These dramatic results demonstrate that dopamine agonists, likepramipexole, represent treatments for cocaine craving, and may beparticularly useful for patients with comorbid refractory depression.

Pramipexole and Other Dopamine Agonists

The synthesis of pramipexole is described in U.S. Pat. No. 4,886,812 andEuropean Patent 186 087. Pramipexole is a non-ergot derivative which maybe used at a range of between about 1.5 mg to 6.0 mg per day, and ispreferably administered between about 1.5 mg and 4.5 mg per day. Higherdosages may be used with the concomitant risk of potential side effects.

Other formulations for treatment or prevention of stimulant dependencyor craving, such as cocaine craving, as described herein, may take theform of a dopamine agonist compound that may be combined with apharmaceutically-acceptable diluent, carrier, stabilizer, or excipient.Conventional pharmaceutical practice is employed to provide suitableformulations or compositions to administer such compositions topatients. Oral administration is preferred, but any other appropriateroute of administration may be employed, for example, parenteral,intravenous, subcutaneous, intramuscular, intracranial, intraorbital,ophthalmic, intraventricular, intracapsular, intraspinal,intracisternal, intraperitoneal, intranasal, or aerosol administration.Therapeutic formulations may be in the form of liquid solutions orsuspensions (as, for example, for intravenous administration); for oraladministration, formulations may be in the form of liquids, tablets orcapsules; and for intranasal formulations, in the form of powders, nasaldrops, or aerosols.

Methods well known in the art for making formulations are described, forexample, in “Remington: The Science and Practice of Pharmacy” (19th ed.)ed. A. R. Gennaro A. R., 1995, Mack Publishing Company, Easton, Pa.Formulations for parenteral administration may, for example, containexcipients, sterile water, saline, polyalkylene glycols such aspolyethylene glycol, oils of vegetable origin, or hydrogenatednapthalenes.

If desired, slow release or extended release delivery systems may beutilized. Biocompatible, biodegradable lactide polymer,lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylenecopolymers may be used control the release of the compounds. Otherpotentially useful parenteral delivery systems include ethylene-vinylacetate copolymer particles, osmotic pumps, implantable infusionsystems, and liposomes. Formulations for inhalation may containexcipients, for example, lactose, or may be aqueous solutionscontaining, for example, polyoxyethylene-9-lauryl ether, glycocholateand deoxycholate, or may be oily solutions for administration in theform of nasal drops, or as a gel.

In general, a dopamine agonist for use in the methods of the inventionis administered at a dosage appropriate to the effect to be achieved andis typically administered in unit dosage form. As noted above, thepreferred route of administration for most indications is oral.

An effective quantity of a dopamine agonist-containing compound of theinvention is employed to treat the stimulant dependency or craving, forexample, cocaine craving as described herein. The exact dosage of thecompound may be dependent, for example, upon the age and weight of therecipient, the route of administration, and the severity and nature ofthe symptoms to be treated. In general, the dosage selected should besufficient to prevent, ameliorate, or treat the condition, or one ormore symptoms thereof, without producing significant toxic orundesirable side effects.

Combination with Other Therapeutics

One particular source of pramipexole is Pharmacia & Upjohn, Inc. whichmarkets Mirapex (Pramipexole Dihydrochloride) tablets which have themolecular structure shown in FIG. 1. Examples of other dopamine agonistsinclude, but are not limited to, amantadine, bromocriptine, cabergoline,lisuride, pergolide, ropinirole, quinpirole, or quinelorane.Pramipexole, or any other dopamine agonist, may be administered as amonotherapy, or in combination with other compounds, for the treatmentof multiple substance abuse or other physiological or psychologicalconditions.

In one particular example, the dopamine agonist (e.g. pramipexole) maybe administered in combination with an antidepressant, anticonvulsant,antianxiety, antimanic, antipyschotic, antiobsessional,sedative-hypnotic, or stimulant medication. Examples of thesemedications include, but are not limited to, the antianxiety medicationsalprazolam, buspirone hydrochloride, chiordiazepoxide, chlordiazepoxidehydrochloride, clorazepate dipotassium, desipramine hydrochloride,diazepam, halazepam, hydroxyzine hydrochloride, hydroxyzine pamoate,lorazepam, meprobamate, oxazepam, prazepam, prochlorperazine maleate,prochlorperazine, prochlorperazine edisylate, and trimipramine maleate;the anticonvulsants amobarbital, amobarbital sodium, carbamazepine,chlordiazepoxide, chlordiazepoxide hydrochloride, clorazepatedipotassium, diazepam, divalproex sodium, ethosuximide, ethotoin,gabapentin, lamotrigine, magnesium sulfate, mephenytoin, mephobarbital,metbsuximide, paramethadione, pentobarbital sodium, phenacemide,phenobarbital, phenobarbital sodium, phensuximide, phenytoin, phenytoinsodium, primidone, secobarbital sodium, trimethadione, valproic acid,and clonazepam; the antidepressants amitriptyline hydrochloride,amoxapine, bupropion hydrochloride, clomipramine hydrochloride,desipramine hydrochloride, doxepin hydrochloride, fluoxetine,fluvoxamine, imipramine hydrochloride, imipramine pamoate,isocarboxazid, lamotrigine, maprotoline hydrochloride, nortriptylinehydrochloride, paroxetine hydrochloride, phenelzine sulfate,protriptyline hydrochloride, sertraline hydrochloride, tranylcyprominesulfate, trazodone hydrochloride, trimipramine maleate, and venlafaxinehydrochloride; the antimanic medications lithium carbonate and lithiumcitrate; the antiobsessional medications fluvoxamine, and clomipraminehydrochloride; the antipsychotic medications acetophenazine maleate,chlorpromazine hydrochloride, chlorprothixene, chlorprothixenehydrochloride, clozapine, fluphenazine decanoate, fluphenazineenathrate, fluphenazine hydrochloride, haloperidol decanoate,haloperidol, haloperidol lactate, lithium carbonate, lithium citrate,loxapine hydrochloride, loxapine succinate, mesoridazine besylate,molindone hydrochloride, perphenazine, pimozide, prochlorperazinemaleate, prochlorperazine, prochlorperazine edisylate, promazinehydrochloride, risperidone, thioridazine, thioridazine hydrochloride;thiothixene, thiothixene hydrochloride, and trifluoperzinehydrochloride; the sedative-hypnotic medications amobarbital,amobarbital sodium, aprobarbital, butabarbital, chloral hydrate,chlordiazepoxide, chlordiazepoxide hydrochloride, clorazepatedipotassium, diazepam, diphenhydramine, estazolam, ethchlorvynol,flurazepam hydrochloride, glutethimide, hydroxyzine hydrochloride,hydroxyzine pamoate, lorazepam, methotrimeprazine hydrochloride,midazolam hydrochloride, non prescription, oxazepam, pentobarbitalsodium, phenobarbital, phenobarbital sodium, quazepam, secobarbitalsodium, temazepam, triazolam, and zolpidern tartrate; and the stimulantsdextroamphetamine sulfate, methamphetamine hydrochloride,methylphenidate hydrochloride and, pemoline.

Other Embodiments

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindependent publication or patent application was specifically andindividually indicated to be incorporated by reference.

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from thepresent disclosure that come within known or customary practice withinthe art to which the invention pertains and may be applied to theessential features hereinbefore set forth, and follows in the scope ofthe appended claims.

Other embodiments are within the claims.

What is claimed is:
 1. A method for treating a human with a stimulantdependency, said method comprising administering to said human atherapeutically effective amount of pramipexole and a therapeuticallyeffective amount of an antidepressant, wherein said pramipexole isadministered intranasally.
 2. A method for treating a human with astimulant dependency, said method comprising administering to said humana therapeutically effective amount of pramipexole and a therapeuticallyeffective amount of an anticonvulsant, wherein said pramipexole isadministered intranasally.
 3. A method for treating a human with acocaine craving dependency, said method comprising administering to saidhuman a therapeutically effective amount of pramipexole and atherapeutically effective amount of an antidepressant, wherein saidpramipexole is administered intranasally.
 4. A method for treating ahuman with a cocaine craving in a human, said method comprisingadministering to said human a therapeutically effective amount ofpramipexole and a therapeutically effective amount of an anticonvulsant,wherein said pramipexole is administered intranasally.
 5. The method ofclaim 2 or 4, wherein said anticonvulsant is lamotrigine.
 6. The methodof any one of claims 1-4, wherein said pramipexole is administered at adose ranging from 1.5 mg/day to 6.0 mg/day.
 7. The method of claim 6,wherein said pramipexole is administered at a dose ranging from 1.5mg/day to 4.5 mg/day.
 8. The method of claim 1 or 2, wherein saidstimulant dependency involves a stimulant craving.
 9. The method of anyone of claims 1-4, wherein said pramipexole is administeredintranasally.